Abstract Sphingolipid Accumulation in the Pancreatic Alpha Cell Links Insulin Resistance to Hyperglycemia This grant evaluates the contribution of lipid metabolite accumulation in the pancreatic alpha cell to the aberrant production of the pancreatic peptide glucagon and glucagon?s ensuing hyperglycemic effects. Pancreatic islets secrete both insulin and glucagon in a manner which is tightly juxtaposed. The hormone glucagon, which promotes hepatic glucose production, has long been underestimated as a contributor to metabolic disease. Diabetes mellitus results from insufficient insulin secretion to match insulin demands by various tissues. This includes a demand by the alpha cell for insulin to diminish glucagon production and secretion. Our preliminary data suggest that impaired insulin action within the alpha cell can promote hyperglucagonemia, which drives hyperglycemia, aberrant gluconeogenesis, and excess glucose efflux from the liver. Sphingolipids, such as ceramides and glucosylceramides, are an important class of bioactive lipids which may impair insulin signal transduction in the alpha cell. Most recently, we demonstrated that ceramide is sufficient to impair insulin-induced suppression of glucagon from alpha cells. The levels of these lipids change as a function of adipose tissue mass and functionality, and are partially driven by cellular availability of palmitoyl-CoA. Aberrant accumulation of sphingolipids has been implicated in a multitude of metabolic processes, including atherosclerosis, insulin resistance, lipotoxic heart failure, beta cell apoptosis and beta cell dysfunction. The adipose-derived secretory factor adiponectin promotes an increase in ceramide catabolism, which is dependent on adiponectin receptors 1 and 2 (AdipoR1/R2). The associated ceramidase activity promotes ceramide degradation and correlates with the suppression of hepatic glucose efflux. Fibroblast growth factor 21 (FGF21, a reported glucagon suppressor), rapidly stimulates adiponectin secretion and improves glycemia by harnessing adiponectin?s ceramide-lowering potential. Preliminary results suggest that novel small molecule mimetics of adiponectin (currently in pharmaceutical development) may offer the same potential therapeutic benefits of adiponectin to improve glucose homeostasis by decreasing ceramide excess and glucagon secretion. Here, we will test the following 3 questions via 3 interrelated aims: 1)Does the alpha cell become insulin, leptin, or GABA resistant in a sphingolipid-dependent manner? 2) Does adiponectin act as a glucagon suppressor via adiponectin receptor-induced ceramidase activity and ceramide-lowering within the alpha cell? 3) Does FGF21 have a direct effect on the alpha cell or does it rely on adiponectin to blunt glucagon secretion? We propose that ceramide within the alpha cell is a key link between insulin resistance and diabetes and serves as a critical physiologic node for regulation of glycemia; this would be a prime target for therapeutic intervention for the treatment and prevention of type-2 diabetes